Trastuzumab Deruxtecan Demonstrates Sustained Efficacy in HER2+ mCRC

Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) demonstrated durable responses and a safety profile that was consistent with findings from the primary analysis of the phase 2 DESTINY-CRC01 trial (NCT03384940) in pretreated patients with HER2-expressing metastatic colorectal cancer (mCRC), according to updated results of the study that were presented at the 2022 Gastrointestinal Cancers Symposium.

In the open-label, multicenter, DESTINY-CRC01 trial, patients were randomized to 3 cohorts: cohort A (n = 53) had patients who were immunohistochemistry (IHC) 3-positive or IHC 2-positive/in situ hybridization (ISH)-positive; cohort B (n = 15) had patients who were IHC 2-positive/ISH-negative; and cohort C (n = 18) had patients who were IHC 1-positive.

Patients in cohort A had an overall response rate (ORR) of 45.3% (95% CI, 31.6%-59.6%), a median duration of response (DOR) of 7.0 months (95% CI, 5.8-9.5), a median progression-free survival (PFS) of 6.9 months (95% CI, 4.1-8.7), and a median overall survival (OS) of 15.5 months (95% CI, 8.8-20.8). No patients remain on treatment.

This study evaluated a total of 86 patients. All cohorts received 6.4 mg/kg of T-DXd every 3 weeks. The primary end point of this study was ORR in cohort A, and the secondary end points were ORR in cohorts B and C, PFS, OS, DOR, disease control rate (DCR), and safety. The median follow-up at the end of the study was 62.4 weeks for cohort A and 27.0 weeks for cohorts B and C.

Eligible patients must have had unresectable and/or mCRC, HER2 expression, RAS/BRAFV600E wild type, and at least 2 prior regimens. Patients were excluded if they had a history of or currently have interstitial lung disease (ILD).

The median age of patients was 58.5 years (27-59), with 46.5% being female. Patients had and ECOG performance score of 0 or 1, with 62.8% scoring 0. The median prior regimens for metastatic disease were 4 (range, 2-11).

DCR among cohorts was 83.0% (95% CI, 70.2%-91.9%) for cohort A, 60.0% (95% CI, 32.3%-83.7%) for cohort B, and 22.2% (95% CI, 6.4%-47.6%) for cohort C. Median treatment duration was 5.1 months (95% CI, 3.9-7.6) for cohort A, 2.1 months (95% CI, 1.4-2.6) for cohort B, and 1.4 months (95% CI, 1.3-1.5) for cohort C.

In a subgroup analysis of cohort A, patients with an ECOG score of 0 (n = 37) had an ORR of 54.1% (95% CI, 36.9-70.5%), and patients with an ECOG score of 1 (n = 16) had and an ORR of 25.0% (95% CI, 7.3%-52.4%). Forty patients with IHC 3+ disease had an ORR of 57.5% (95% CI, 40.9%-73.0%). Those with IHC 2+/ISH+ disease (n = 13) had an ORR of 7.7% (95% CI, 0.2%-36.0%). Sixteen patients had prior HER2 treatment and had an ORR of 43.8% (95% CI, 19.8%-70.1%), and 37 patients without prior HER2 treatment had an ORR of 45.9% (95% CI, 29.5%-63.1%).

Safety data remained consistent with what is known for T-DXd from previous studies. Overall, 65.1% of patients experienced grade 3 and higher treatment emergent adverse events (TEAEs). Overall, 13 patients (15.1%) had TEAEs leading to drug discontinuation, 15 patients (17.4%) had TEAEs leading to dose reduction, and 34 patients (39.5%) had TEAEs leading to drug interruption. Nine patients (10.5%) had TEAEs associate with death.

Investigators noted patients with ILD/pneumonitis AEs. Eight patients (9.3%) had adjudicated drug-related ILD/pneumonitis. Median time to adjudicated onset was 61.0 days (range, 9-165). Of these 8 patients, 4 had grade 2, 1 had grade 3, and 3 had grade 5 AEs. All 8 patients received corticosteroids in response. The 4 patients with grade 2 recovered, and the patients with grade 3 did not recover due to later disease progression. The 3 patients with grade 5 ILD/pneumonitis died with a median onset of 22.0 days (9-120), and death occurred 6 to 9 days after diagnosis.

These promising results support continued research of T-DXd in patients with HER2-positive mCRC while the risk of potential ILD/pneumonitis requires monitoring.

Reference

Yoshino T, Di Bartolomeo M, Raghav K, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). Presented at: 2022 Gastrointestinal Cancers Symposium; January 20-22, 2022; San Francisco, CA. Abstract 119.